ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3737C>T (p.Thr1246Ile) (rs397508600)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668850 SCV000793522 uncertain significance Cystic fibrosis 2017-08-25 criteria provided, single submitter clinical testing
Mendelics RCV000668850 SCV000886147 uncertain significance Cystic fibrosis 2020-08-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781266 SCV000919178 likely pathogenic not specified 2018-05-03 criteria provided, single submitter clinical testing Variant summary: CFTR c.3737C>T (p.Thr1246Ile) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) domain and AA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245736 control chromosomes (gnomAD). The variant, c.3737C>T, has been reported in the literature in two individuals affected with Non-classic Cystic Fibrosis together with F508del (Goubau_2009, Sosnay_2017), and in one patient with CF/CBAVD (Claustres_2000). In addition, 23 patients are listed in the CFTR2 database, some of which are reported to carry the variant along with a CF-causing variant and have CF. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, though a study on channel dynamics suggested the Thr1246 codon is a critical residue for function (Vergani_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. It was reported in publications and databases that patients with this variant and with a known CF-causing variant may or may not have CF, indicating they could have a mild phenotype occurring later in life, with a risk for developing P. Aeruginosa infections and pancreatic insufficiency (SickKids and CFTR2 databases, Sosnay_2017). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000668850 SCV001425315 pathogenic Cystic fibrosis 2020-04-27 criteria provided, single submitter clinical testing CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287675 SCV001474386 likely pathogenic none provided 2020-07-09 criteria provided, single submitter clinical testing The CFTR c.3737C>T; p.Thr1246Ile variant (rs397508600) is reported in the literature in the compound heterozygous state with a different pathogenic variant in individuals affected with cystic fibrosis, a CFTR-related disorder, or borderline sweat chloride levels with no other significant symptoms (Claustres 2000, El-Seedy 2012, Goubau 2009, Masica 2015, Sermet-Gaudelus 2010, Sosnay 2017). This variant is reported in ClinVar (Variation ID: 53799), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1246 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses of the variant protein demonstrate 13% of wild-type function, consistent with an intermediate effect (Raraigh 2018). Based on available information, this variant is considered to be likely pathogenic with variable clinical consequences. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR, White TB, Farrell PM, et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2.
Invitae RCV000668850 SCV001590786 pathogenic Cystic fibrosis 2020-08-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1246 of the CFTR protein (p.Thr1246Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs397508600, ExAC 0.002%). This variant has been observed in individual(s) with congenital bilateral absence of the vas deferens and individuals with cystic fibrosis (PMID: 28129813, 10923036, 22678879). This variant has also been reported with another CFTR variant in individuals with intermediate sweat chloride results (PMID: 19318346, 20538955). ClinVar contains an entry for this variant (Variation ID: 53799). This variant has been reported to affect CFTR protein function (PMID: 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic.

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